Diffuse large B-cell lymphoma (DLBCL) account for approximately 40% of adult non-Hodgkin lymphomas. It is clinically, morphologically and genetically a heterogeneous group of tumors composed of large B cells. Two main, prognostically different subgroups of DLBCL were identified by distinct gene expression profiles either characteristic of normal germinal center B-cells or of activated blood memory B-cells. The germinal center B-cell-like (GCB-like) subgroup was correlated with a significantly better prognosis in comparison to the activated B-cell-like (ABC-like) subgroup. As such, 76% of GCB-like DLBCL patients were still alive after five years, as compared with only 16% of ABC-like DLBCL patients. In addition to differential expression of coding genes, ABC-type lymphoma cells express high levels of the non-coding microRNA miR-155, an onco- miR whose ectopic expression has been previously shown to give rise to B cell malignancies. In our preliminary studies, we identified the inositol-phosphatase SHIP as the first bona-fide target of miR-155. Interestingly, we had also found recently that concomitant ablation of both Ship and Pten in murine B cells (bPten/Ship-/-) induces lethal lymphoma resembling DLBCL with 100% penetrance, revealing a novel role for SHIP as a tumor-suppressor. Our preliminary results further demonstrate that elevated levels of miR-155, and consequent abrogation of SHIP expression, are mediated through autocrine stimulation of ABC-type DLBCL cells via TNFa, a proinflammatory cytokine whose serum levels are known to be elevated in DLBCL patients. We therefore hypothesize that elevated TNFa levels lead to attenuated expression of the tumor suppressor SHIP though induction of miR-155. The goal of this proposal is to 1) further characterize the molecular interplay between TNFa, miR-155 and SHIP, 2) to investigate the role of inflammatory responses in lymphomagenesis, and 3) to test the feasibility of anti-TNFa regimen (Remicade(r)., Enbrel(r).) as a novel supporting treatment for DLBCL. DLBCL is the most common B cell non-Hodgkin's Lymphoma, with > 25,000 new cases in the US every year. While treatment efficacy for certain subgroups has improved over recent years, the prognosis for ABC-type DLBCL is still poor. The studies presented in this application will investigate a novel theory on the etiology and progression of DLBCL, and likely lay the foundation for new treatment strategies. PUBLIC HEALTH RELEVANCE: DLBCL is the most common B cell non-Hodgkin's Lymphoma, with > 25,000 new cases in the US every year. While treatment efficacy for certain subgroups has improved over recent years, the prognosis for ABC-type DLBCL is still poor. The studies presented in this application will investigate a novel theory on the etiology and progression of DLBCL, and likely lay the foundation for new treatment strategies. [unreadable] [unreadable] [unreadable]